Granulate for the formulation of orodispersible tablets

ABSTRACT

This invention relates to a granulate comprising mannitol and sorbitol in a weight ratio of between 70:30 and 97:3. This invention also relates to the use of the said granulate in the preparation of orodispersible tablets, to the orodispersible tablets obtained with the said granulate and to a process of production for obtaining the said granulate.

FIELD OF THE INVENTION

This invention relates to a granulate for the formulation oforodispersible tablets, in particular the formulation of orodispersibletablets comprising pharmaceutical or nutritional active ingredients.

In particular this invention relates to a granulate comprising mannitoland sorbitol in a weight ratio between 70:30 and 97:3. This inventionalso relates to the use of the said granulate in the preparation oforodispersible tablets, to orodispersible tablets obtained using thesaid granulate and to a production process for obtaining the saidgranulate.

The orodispersible tablets obtained using the granulate according tothis invention have high porosity and may comprise a high content of theactive ingredient in comparison with the orodispersible tablets known inthe art.

STATE OF THE ART

Orodispersible (OD) tablets are tablets taken orally which rapidlydisintegrate in the mouth through the effect of the solvent action ofsaliva and the mechanical action of the tongue. OD tablet formulationshave better acceptability than traditional swallowable tablets, both inpatients having difficulty with swallowing such conventional tablets(for example young children and the elderly), and patients withgastro-intestinal syndromes, who have greater problems in absorbing theactive ingredients from solid pharmaceutical forms taken orally, whichmay be disturbed by the presence of the still undissolved solid tabletwithin the gastro-intestinal tract.

The disintegration of an OD tablet does not take place through a singlemechanism, but involves various phenomena such as swelling of thedisintegrant in contact with saliva, the formation of small channelspromoted by the presence of pores in the tablet, the presence ofeffervescent substances, the mechanical action of the tongue, and so on.

In any event, the penetration of water (saliva) within an OD tablet isthe first and fundamental step to disintegration, and for this it isnecessary to find a compromise between the physical characteristics ofthe tablet and the chemical properties of the excipients used in theformulation.

U.S. Pat. No. 6,149,938 relates to a process for obtaining a usefulgranulate for the production of a solid form for oral use which rapidlydisintegrates in the buccal cavity. This granulate is prepared by thefluidised bed granulation of an aqueous solution comprising awater-soluble or water-dispersible polymer and a polyalcohol, which mayoptionally be mixed with other solid components, and subsequent dryingin a fluidised bed dryer. The polyalcohol preferably used is sorbitol,but others such as mannitol, xylitol, maltitol and so on may also beused; the quantity of polyalcohol varies between 50% and 90% by weightwith respect to the total weight of the tablet obtained by compressionof the granulate. The tablets described in the examples includelubricants, have a weight of between 1 and 2 grams, and a disintegrationtime of between 30 and 140 seconds.

Despite the fact that the Official Pharmacopoeia has used the term ODtablets to define tablets which disperse in the mouth within 3 minutesbefore swallowing, the US FDA has defined OD tablets as a solid formcontaining an active ingredient which disintegrates rapidly, normally ina matter of seconds, when placed on the tongue. Generally thedisintegration of an OD tablet occurs between a few seconds andapproximately one minute (Bandari et al., “Orodispersible tablet: Anoverview”, Asian Journal of Pharmaceuticals, January 2008). Taking atime of 20-30 seconds as a commercially acceptable value for thedefinition of fast disintegration, no tablets having a mass of more than600 mg are found on the market because increased mass makes it difficultfor saliva to penetrate the tablet and therefore inhibits the functionof the disintegrants, with consequent slowing of disintegration.

Conventional OD tablets (as for example described in WO 03/009830 and inWO 00/27357) always include at least one disintegrant which swells as aresult of water absorption and/or water channelling. However, thepresence of a disintegrant, which is necessary for the disintegration ofconventional OD tablets, has two disadvantages—on the one hand itincreases the mass of the tablet restricting the possibility of addingthe active ingredient in larger doses, and on the other it absorbssaliva, leaving a dry feeling in the oral cavity.

EP 1 800 669 relates to a solid pharmaceutical composition comprising acentral core containing the active ingredient and excipients for anorodispersible formulation and an orodispersible coating, for the oral,oral mucosal or sublingual administration of agomelatin. In more detail,the orodispersible coating is obtained with a specific diluent fororodispersible preparations, or using a conventional diluent with one ormore added disintegrants. The orodispersible diluent may comprisegranules obtained by the co-atomization of lactose and starch(Strarlac®), or a atomized polyalcohol, for example sorbitol ormannitol, or a atomized mixture based on polyalcohols, for exampleexcipients commercially marketed such as Partek® and Pharmaburst®. In ODtablets prepared using this method and described in the examples thepolyalcohol used is mannitol for direct compression or Starlac®. Thetablets obtained using this method have a maximum weight of 350 mg andin vitro tests describe a disintegration time of less than 3 minutes.

The methods of preparation described above for the production of ODtablets (for example in WO2007/104771 and U.S. Pat. No. 5,866,163)include both methods used for the production of conventional tablets andalternative methods, such as fusion or lyophilisation processes inmoulds, which are already known to those skilled in the art. Theproduction of OD tablets requires suitably designed manufacturing unitsbecause of the poor mechanical properties of the tablets. Lubricantshave to be added to increase the compressibility and flowability of thepowders, but there is the disadvantage that these excipients reduce thewettability of the tablet and therefore the rate of disintegration.

SUMMARY OF THE INVENTION

The object of this invention is to provide a granulate for theformulation of orodispersible tablets which overcomes the problemsdescribed.

In the course of extensive experimentation the Applicant has had to makea selection of components considering various parameters such as, forexample, speed and safety of manufacture, compressibility, palatability,stability, food intolerances, solubility, purchase cost and availabilityon the market.

The Applicant has found that a granulate comprising mannitol andsorbitol in a specific weight ratio makes it possible to manufacture ODtablets which disintegrate rapidly, in times less than 30 seconds, incontact with saliva in the oral cavity, with good palatability.

Surprisingly the Applicant has found that the granulate according tothis invention obtained from the combination of mannitol and sorbitol,two readily available and inexpensive polyalcohols, has made it possibleto obtain an OD tablet which at the same time disintegrates and/ordissolves in the oral cavity without the need to add a disintegrant.

The absence of disintegrants and the presence of polyalcohols ensuresthat the tablets are more palatable. In fact in conventional OD tabletsthe quantity of disintegrant is such that it completely absorbs thesaliva present in the oral cavity, because the water absorbtion capacityof these excipients varies between 3 and 10 times their weight, leavingthe patient treated with a feeling of dryness in the mouth (plastereffect).

Mannitol and sorbitol are highly hygroscopic and soluble in water, whichis essential for oral administration where the quantity of liquid(saliva) available for disintegration is fractions of a milliliter.

The Applicant has surprisingly found that OD tablets obtained with thegranulate according to this invention may have a very much greater mass,up to 2000 mg and even more, in comparison with conventional OD tabletscomprising a disintegrant, whilst keeping disintegration times below 30seconds.

The Applicant has therefore observed that the possibility of obtainingtablets having a mass of more than 2 g also includes the possibility ofadding a greater quantity of the active ingredient to the formulation incomparison with conventional tablets.

In addition to this, the increase in tablet size makes it possible toapply less pressure per unit surface area during the compression step,and as a consequence to obtain greater porosity.

The Applicant has found that the granulate according to this inventionhas good mechanical properties, with high compressibility andflowability, which means that it can be used without the addition oflubricating agents.

Thus, in a first aspect, this invention relates to a granulate of amixture of mannitol and sorbitol in a ratio by weight of betweenapproximately 70:30 and approximately 97:3.

The Applicant has found that use of the granulate according to thisinvention makes it possible to obtain tablets with a highcompressibility index. The compressibility index is given by the ratiobetween the hardness of the tablet and the compression force. For thesame compression force the tablets obtained using the granulateaccording to this invention have greater hardness and lower density.Greater hardness imparts the necessary strength upon the tablet towithstand mechanical stresses during the processes of production andpackaging without breaking up. Lower density imparts greater porosity onthe tablet and therefore a greater rate of disintegration because waterpenetrates within the OD tablet more quickly.

Thus, in a second aspect, this invention relates to an OD tabletcomprising a granulate of a mixture of mannitol and sorbitol in a ratioby weight of between approximately 70:30 and approximately 97:3.

The Applicant has also observed that the characteristics of thegranulate according to this invention are advantageously obtainedthrough a fluidised bed granulation process by controlling thedimensions of the mannitol and sorbitol particles, the quantity ofwater, and the temperature and humidity of the air used in thegranulation process.

Thus, in a third aspect, this invention relates to a process forproducing a granulate comprising mannitol and sorbitol, the said processcomprising the following steps:

-   (i) providing mannitol and sorbitol in the form of powder,    preferably having an average particle size of less than 100 μm and    between 200 μm and 250 μm respectively,-   (ii) providing a mixture of the said mannitol and the said sorbitol    in a ratio by weight of between approximately 70:30 and    approximately 97:3,-   (iii) introducing the said mixture into a fluidised bed granulator,-   (iv) granulating the said mixture under the following conditions:    -   (a) spraying a quantity of water of between 5% and 35% by weight        with respect to the weight of the said mixture, and    -   (b) introducing air at a temperature below 80° C. with a        moisture content of less than 5000 ppm, preferable equal to or        lower than 1000 ppm.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the in vitro and in vivo disintegration times of tablets 10according to the invention as a function of hardness, and comparisontablets 11 described in Example 5 below.

DETAILED DESCRIPTION OF THE INVENTION

In at least one of the aforesaid aspects this invention may show one ormore of the preferred characteristics described below.

Preferably the granulate according to this invention comprises mannitoland sorbitol in a ratio by weight of between 80:20 and approximately95:5, and even more preferably approximately 90:10.

Advantageously the granulate according to this invention has an averageparticle size of between 50 μm and 500 μm, preferably between 150 μm and350 μm. For values below 50 μm the granulate tends to become compactedbecause of prevalence of weak forces (of the Van der Waals,dipole-dipole and hydrogen bond type) over the weight force of theparticle and low flowability problems occur. At values over 500 μm thegranulate shows an increase in the inter-particle empty spaces, whichincreases the apparent volume. Apparent volume is defined as the spaceoccupied by a particular quantity of granulate when poured and caused tofall into a container of cubic or rhomboidal shape. As the apparentvolume increases, there is an increase in flow time, the time whichreflects the ease of which the granulate becomes distributed in thecontainer. As the apparent volume and flow time increase, thevariability in the time required by the granulate to fill the rhomboidalcontainer and the cubic container increases.

According to a preferred aspect the granulate according to thisinvention has a density of less than 1 g/cm³, and more preferably lessthan 0.75 g/cm³.

The low density of the granulate is an indication of its high porosity,and makes it possible to obtain OD tablets with reduced disintegrationtimes, increased hardness (imparting the ability to withstand mechanicalstresses) and good compressibility.

Advantageously the granulate according to this invention has a very lowresidual moisture content, less than 0.20% by weight relative to theweight of the granulate. More preferably the granulate according to thisinvention has a residual moisture content equal to or lower than 0.10%by weight relative to the weight of the granulate.

The Applicant has observed that for residual moisture values slightlyabove that specified (up to 0.50%) there are increases in the hardnessof the tablets over time which have an adverse effect on the rate ofdisintegration in the mouth, while at residual moisture values wellbeyond those specified (up to 1.00% and more) the stability of the finaltablet is compromised.

The granulate according to this invention is prepared using a fluidisedbed granulation technique. Under specific conditions this type ofgranulation makes it possible to obtain the product with the desiredcharacteristics.

The process of producing the granulate according to this inventioncomprises the following steps:

-   (i) providing mannitol and sorbitol in the form of powder,    preferably having an average particle size of less than 100 μm and    between 200 μm and 250 μm respectively,-   (ii) providing a mixture of the said mannitol and the said sorbitol    in a ratio by weight of between approximately 70:30 and    approximately 97:3,-   (iii) introducing the said mixture into a fluidised bed granulator,-   (iv) granulating the said mixture under the following conditions:    -   (a) spraying a quantity of water of between 5% and 35% by weight        with respect to the weight of the said mixture, and    -   (b) introducing air at a temperature below 80° C. with a        moisture content of less than 5000 ppm, preferable equal to or        lower than 1000 ppm.

The Applicant has observed that the use of a mixture of mannitol andsorbitol having an average mixture particle size of less than 200 μm,preferably between 100 μm and 150 μm, makes it possible to obtain afinal granulate having a greater compressibility index. Because mannitolis always the main component in the mixture (in a quantity of between70% and 97% by weight) with respect to sorbitol, which is always thesecondary component (in a quantity between 30% and 3% by weight), thelatter may also be used in the form of a powder having an averageparticle size of more than 200 μm. In particular the Applicant has foundthat better results are obtained with a mixture comprising mannitolhaving an average size of less than 100 μm and sorbitol having anaverage size between 200 μm and 250 μm.

In addition to this, the Applicant has observed that the use of water asa solvent makes it possible a better granulation and workability of thetwo polyalcohols, in addition to being non-toxic and non-hazardous.

Advantageously the preferred quantity of water is between 10% and 30% byweight, more preferably between 15% and 25% by weight with respect tothe weight of the mixture of mannitol and sorbitol in the said mixture.

Preferably the temperature of the air introduced into the fluidised bedgranulator is higher than 60° C., more preferably between 65° C. and 75°C., and even more preferably around 70° C. The relative moisture contentof the air introduced into the fluidised bed granulator is less than5000 ppm, preferably equal to or lower than 1000 ppm.

The Applicant has observed that temperatures equal to or higher than 80°C. may cause chemical and physical changes in the granulate, with theoccurrence of fusion and yellowing. On the other hand the Applicant hasobserved that temperatures below 60° C. would require long drying times,which, although in principle practicable, are not convenient from theindustrial point of view. In particular the Applicant has observed thatoptimum drying times from the industrial point of view are less than 30minutes, preferably equal to or lower than 20 minutes. The choice ofrelative humidity values for the air introduced into the fluidised bedgranulator also depends on drying temperature and times, and the desiredresidual moisture content.

The granulate obtained through the process according to this inventionhas perfect flowability and has a regular particle size which permitsprecise dosing.

The granulate obtained through the process according to this inventionalso has high compressibility.

Compressibility is measured as the ratio between the hardness of thetablet and the compression force applied in order to obtain thathardness. This ratio is defined as the “Compressibility Index” (CI).

The Applicant has found that the granulate according to this inventionhas a compressibility index of more than 4.5, a value which is not foundwith other known excipients for the production of orodispersibletablets.

A high CI value means that greater hardness can be obtained with lesscompression force. This avoids the addition of a lubricant among theexcipients, which, as known to those skilled in the art, is used toprevent the granulate to stick to the punches and walls of the mouldduring the compression step and ensures that the particles comprisingthe granulate can flow.

Applying less compression forces also means obtaining a lower densityand as a consequence greater porosity in the tablet so obtained. Thismeans a greater rate of water penetration and a shorter disintegrationtime.

Other factors being the same, the possibility of obtaining greaterhardness imparts better mechanical properties on the tablets, whichensures less problems during the steps of production and packaging ofthe final pharmaceutical form.

This invention also relates to an OD tablet comprising the granulateaccording to this invention.

Advantageously the tablet according to this invention comprises at least50% by weight of granulate, preferably between 50% and 99% by weight.The presence of a quantity of granulate of more than 50% by weightensures a good compression yield regardless of the mechanicalcharacteristics of the active ingredient used, and makes it possible toachieve good compression yields even with difficulty compressible activeingredients. Below this percentage the compression yield may decreaseappreciably because of the lack of contact between the particles of thegranulate according to this invention.

The Applicant has also observed a further advantage of the tabletsaccording to this invention which is correlated with the absence ofdisintegrants.

In general it is observed that for constant compression and hardnesstablets show a decrease in density corresponding to an increase inweight, and therefore an increase in their volume and porosity.Technically, if the values of density (Y) and weight (X) of a tabletobtained at constant pressure are plotted on a system of coordinates itwill be observed that the resulting straight line has a negative angularcoefficient. Lines which are all parallel to each other are obtained fordifferent pressure values.

In conventional tablets which contain disintegrants the increase in masshas nevertheless a limit associated with both the length of the routewhich the water (saliva) has to travel in order to penetrate within thetablet and promote the disintegrant's swelling mechanism, and thequantity of water (saliva) available within the oral cavity.

On the contrary the phenomenon of increased porosity with increasedvolume results in an advantage for tablets according to this invention.

The Applicant has in fact observed that using the granulate according tothis invention the mass of the tablets is greater, and the rate ofdisintegration is also greater. This happens because disintegration ofthe tablet according to the invention depends only on contact betweenthe granulate and water (saliva). Because the latter can penetrate thetablets with greater porosity more quickly, the volume and as aconsequence the mass of the tablets can be increased without acorresponding increase in disintegration times.

The tablets according to this invention may comprise any activeingredient which is suitable for oral administration. Examples of theactive ingredients which may be advantageously used in preparing tabletsaccording to this invention are non-steroidal anti-inflammatory drugs(NSAIDs), anxiolytics, antiemetics, antihistaminics, proton pumpinhibitors, and so on.

The active ingredients formulated in OD tablets may advantageously becoated with one or more layers of a polymer, either to mask theunpleasant taste of the active ingredient or to obtain gastricprotection or prolonged/delayed release over time. Examples of polymerswhich are advantageously used to coat the active ingredients used inpreparation of the tablets according to this invention are for exampleEudragit (Evonik), Methocel (Dow), Kollicoat (BASF), Klucel (Signet),Aqualon, Aquacoat, Lustreclear (FMC), Opadry (Colorcon), Spectracel,Spectrablend (Sen-sient).

These polymeric coatings are fragile in the compression step. Thecompression materials and methods conventionally used requires highcompression forces which can compromise the integrity and as aconsequence the function of the coating. As a result of its highcompressibility the granulate according to this invention makes itpossible to reduce the risk of breakdown of the polymer coating becauseno high compression force is required. In particular the Applicant hasobserved that the granulate according to this invention has an ultimatestrength which is five times less than the ultimate strength for thecoating polymer.

In addition to this the use of a high percentage of granulate accordingto this invention, equal to at least 50% of the weight of the tablet,reduces adhesion phenomena by limiting contact between the granules ofcoated active ingredient and as a consequence the coating function isnot compromised.

The tablet according to this invention may also comprise otheringredients typically used in the preparation of orodispersible tabletssuch as for example diluents, sweeteners, flavourings and the like.

Examples of suitable diluents comprise lactose, starch, dextrose,xylitol, and so on.

Examples of suitable sweeteners comprise aspartame, saccharin,acesulphame, and so on.

Examples of suitable flavourings comprise grapefruit flavour, raspberryflavour, lemon flavour, orange flavour, caramel flavour, vanillaflavour, cream flavour, and the like.

The following examples are intended to illustrate preferred aspects ofthe invention, without nevertheless having the object of restricting it.Those skilled in the art will be able to find various modificationswhich fall within the spirit of the invention and the scope of theclaims.

Example 1

A mixture of powdered mannitol (average size less than 100 μm) andpowdered sorbitol (average size between 200 μm and 250 μm) in a weightratio of 9:1 was used to prepare the granulate using differentgranulation methods.

Using the dry granulation technique, the mixture was first compacted bya tablet press into slugs having a diameter of approximately 20-30 mm.Using different compression forces, slugs T_(A), T_(B), T_(C) havingrespective hardness of 20N, 50N and 120N were obtained. The slugs werethen broken up using an oscillating granulator and sieved through a 1000μm sieve. Granulates A, B and C obtained from slugs T_(A), T_(B), T_(C)respectively had the average sizes and densities indicated in Table 1.

Using the wet granulation technique, the mixture was wet granulated withpurified water in an Erweka AR400 granulator. The paste was dried on afluidised bed and sieved through a 1000 μm mesh. Granulate D had anaverage size and density as indicated in Table 1 below.

Using the fluidised bed technique, the mixture was introduced into aGlatt WCG-CD200 fluidised bed granulator together with dry hot air at70° C. (residual moisture content less than 1,000 ppm) and purifiedwater was sprayed in a quantity of approximately 20% by weight withrespect to the weight of the mixture. Granulate E had an average sizeand density as indicated in Table 1 below.

TABLE 1 Granulate Density Average size A 0.606 259 B 0.645 234 C 0.714231 D 0.921 221 E 0.513 242

The five granulates A-E so obtained were used to prepare respectivelyfive tablets 1-5 in a dose of 2.6 g in a tablet press equipped withpunches having a diameter of 25 mm exerting a compression force of 65KN. The hardness and thickness values for the tablets so obtained areshown in Table 2 below.

TABLE 2 Tablet Hardness (N) Thickness (mm) 1 90 4.6 2 90 4.6 3 100 4.5 4160 4.3 5 300 4.6

The data in Table 2 clearly show that granulate E according to thisinvention makes it possible to obtain tablets with a greater hardnessfor the same compression force.

Example 2

Granulate E according to this invention was compared with a series ofcommercial excipients ready for compression. The comparison was made bycomparing a series of tablets as described in Example 1 and measuringthe resulting hardness of each tablet obtained. The results aresummarised in Table 3 below.

TABLE 3 Excipient Hardness (N) CI Granulate E 300 4.62 Xylitab 200(Danisco) 285 4.38 Sorbitol (Roquette) 245 3.77 Maltodextrin 215 3.31Isomalt (Diamalt) 214 3.29 Emdex (Mendell) 212 3.26 Ercawax 4000 (Erca)196 3.02 Pearlitol (Roquette) 163 2.51 Lactose DC 105 1.62 Microtal(T&L) 92 1.42 Saccharose 75 1.15 Fructose 50 0.77 Citric acid 45 0.69

The data in Table 3 showed that granulate E has the best compressibilityindex (CI) in comparison with the excipients known in the art.

Example 3

Granulate E according to this invention was prepared following theprocedure described in Example 1, varying the process conditions(temperature and humidity) of the air. The results are summarised inTable 4 below.

TABLE 4 Relative Temperature (° C.) humidity (%) Result 80 0.1Non-conforming product- product melted and turned to yellow 70 0.1Optimum product - moisture content 0.1% after 20 minutes drying 50 0.1Non-conforming product - product moisture content 0.25% after 50 minutesdrying (long) 70 1 Conforming product - product moisture content 0.20%after 60 minutes drying (long) 70 10 Conforming product - productmoisture content 0.20% after 70 minutes drying (long) 70 25Non-conforming product - product moisture content 0.25% after 70 minutesdrying (long)

Example 4

Three test granulates F-H were prepared using the procedure described inExample 1, but varying drying times so as to obtain a different residualmoisture content, as shown in Table 5.

TABLE 5 Residual moisture Granulate Time (minutes) content (%) F 20 0.11G 10 0.26 H 0 0.78

The three granulates F-H so obtained were used to prepare three lots oftablets 6-8 respectively with a dosage of 2.6 g in a tabletting machinehaving punches of diameter of 25 mm exerting a compression force of 65KN. The hardness values of the tablets so obtained were measuredimmediately after preparation (T0), after one month (T1), and afterthree months (T3). Table 6 below summarises the values obtained.

TABLE 6 Hardness (N) Tablet T0 T1 T3 6 291.6 300.4 288.7 7 290.0331.2 >350 8 294.1 * * * The tablet in lot 8 was already degraded at onemonth

The data in Table 6 clearly showed that the residual moisture content ofthe granulate has an appreciable effect on the hardness of the tabletsover time. The tablets in comparison lots 7 and 8 proved unusable onemonth and/or three months after preparation. The increased hardness ofthe tablets in lot 7 had an adverse effect on the disintegration rate inthe mouth while the tablets in lot 8 were already degraded after onemonth. The tablets in lot 6 obtained from granulate according to thisinvention showed constant values for hardness over time and nodegradation.

Example 5

Granulate E according to this invention was used to prepare tablets ofdifferent hardness in the presence or absence of disintegrants as shownin Table 7.

TABLE 7 Tablet Ingredients (mg) 10a 10b 11a 11b Granulate E 1000 1000925 925 Avicel PH200 — — 50 50 Kollidon CL — — 25 25 Hardness (N) 25 4525 45

The disintegration time for each tablet was measured using the in vitromethod according to the European Pharmacopeia, and the in vivo method.The results are summarised in Table 8 below.

TABLE 8 Disintegration time (seconds) Tablet Hardness In vitro method Invivo method 10a (i) 25 40 15 10b (i) 45 100 25 11a (c) 25 30 20 11b (c)45 55 50

The data in Table 8 showed that the in vitro method according to theEuropean Pharmacopoeia does not predict the in vivo behaviour of tablets10 according to this invention.

In fact, in vitro tablets 10 according to the invention showed anincrease in disintegration time with increased hardness (from 40 to 100seconds) and in all cases always longer than the disintegration time ofcomparison tablets 11 (30 and 55 respectively). Wholly negative resultswere also expected from the in vivo test following these results.

Vice-versa, in vivo, comparison tablets 11 behaved consistently with thein vitro results, with similar disintegration times (20 and 50respectively), while tablets 10 according to the invention showedcompletely different and positive disintegration times, much shorterthan those for tablets 11 (15 and 25 respectively).

The graph in FIG. 1 shows the different trends shown by tablets 10according to the invention and comparison tablets 11, in vitro and invivo respectively, with increasing hardness.

Example 6

Granulate E according to this invention was used to prepare two seriesof tablets in the presence or absence of disintegrants as shown in Table9. The tablets used in the test were produced in order to simulate atablet containing an active ingredient (not actually present) whichwould require a coating (for example in order to mask its unpleasantflavour). Syloid FP, sodium lauryl sulphate, stearic acid and EudragitEpo were used to prepare the polymer coating.

TABLE 9 Tablet Ingredients (mg) 12 (c) 13 (i) Base for deposition of theactive ingredient Polysorbate 20 1.0 1.0 Simeticone dry 1.0 1.0 Sugarspheres 60 250.0 250.0 Coating film Syloid FP 30.2 30.2 Sodium lauryl4.0 4.0 sulphate Stearic acid 6.0 6.0 Eudragit Epo 40.3 40.3Disintegrants Avicel pH200 75.0 — Kollidon CL 25.0 — Other excipientsAspartame 15.0 15.0 Caramel flavour 20.0 20.0 Granulate E 532.4 632.4Total weight 1,000.0 1,000.0

(i) Invention

(c) Comparison

Tablets 12 and 13 were used in a test panel of 25 volunteers to checkthe in vivo disintegration rate and to have an objective evaluation ofthe palatability of the product. The organolectic characteristics aboutwhich the participants in the test had to give their opinion were thefollowing:

-   -   ease of swallowing    -   dry feeling in the mouth    -   persistent presence of residue    -   ease of disintegration    -   overall satisfaction

In order to express their feelings the participants in the test wereinstructed to use the scale shown in Table 10 and to take the tabletswithout water and without chewing. The tablets were distributed blind.

TABLE 10 Score Meaning 0 None 1 Very little 2 Little 3 Some 4 Much 5Very much

Table 11 below shows the results obtained.

TABLE 11 13 (i) 12 (c) Average Standard Average Standard value deviationvalue deviation Disintegration time (sec) 11.5 3.3 20.0 4.7 Ease ofswallowing 4.8 0.4 4.5 0.7 Dryness of the mouth 0.5 0.7 1.9 0.9 Presenceof residue 0.4 0.7 1.2 0.9 Ease of disintegration 4.9 0.3 4.5 0.5Overall satisfaction 4.8 0.5 4.1 0.7

The results were collected and analysed by statistical processing usingthe t test (two tail α=0.05) through which the means of the valuesobtained can be compared. Given a first value for the mean and itsstandard deviation, this method can be used to check whether this firstmean value differs from another mean value obtained. The disintegrationtime for tablets 13 according to the invention proved to besignificantly less than the disintegration time for comparison tablets12 containing disintegrants. In addition to this, tablet 13 according tothe invention proved to be more acceptable overall, with adisintegration time of almost 50% less than that of comparison tablet12.

1-12. (canceled)
 13. A process for the production of a granulatecomprising mannitol and sorbitol, comprising: (i) providing mannitol andsorbitol in the form of powder, (ii) mixing said mannitol and the saidsorbitol in a ratio by weight of between approximately 70:30 andapproximately 97:3, (iii) introducing said mixture into a fluidised bedgranulator, (iv) granulating said mixture under the followingconditions: (a) spraying a quantity of water of between 5% and 35% byweight with respect to the weight of said mixture, and (b) introducingair at a temperature below 80° C. with a moisture content of less than5000 ppm.
 14. The process according to claim 13, wherein said mannitolhas an average particle size of less than 100 μm and said sorbitol hasan average particle size of between 200 μm and 250 μm.
 15. The processaccording to claim 13, wherein said mixture has an average particle sizeof less than 200 μm.
 16. The process according to claim 13, wherein saidmixture has a ratio by weight between said mannitol and said sorbitolbetween approximately 80:20 and approximately 95:5.
 17. The processaccording to claim 13, wherein the quantity of water is between 15% and25% by weight with respect to the weight of the mixture.
 18. The processaccording to claim 13, wherein said air has a temperature between 65° C.and 75° C.
 19. The process according to claim 13, wherein said air has amoisture content equal to or lower than 1000 ppm.
 20. The processaccording to claim 15, wherein said mixture has an average particle sizeof between 100 μm and 150 μm.